Over the past decades, the American Joint Committee on Cancer (AJCC) has established a well-defined system for cancer staging based on 3 key components: local tumor extent (T stage), dissemination to the regional lymph nodes (N stage), and metastatic spread to distant sites (M stage) (TNM staging).¹ The AJCC TNM staging system attempts to use anatomical and reproducible parameters to discriminate groups with different survival outcomes.^1-4 Reliable prediction of survival estimates is of paramount importance in cancer care. Accurate prognostication helps clinicians in guiding treatment decisions, provides researchers with a tool to adjust for cancer stage in evaluating treatment outcomes, and is informative to patients themselves.^5,6

BACKGROUND: Fibrosis is a cardinal feature of small intestinal neuroendocrine tumors (SI‐NETs) both in local peritumoral tissue and systemic sites (cardiac). 5‐HT, a commonly secreted NET amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the tumor microenvironment are unclear. We hypothesized that targeting 5‐HT_2Breceptors on tumor cells would inhibit SI‐NET 5‐HT release and, thereby, fibroblast activation in the tumor microenvironment.METHODS: We studied the 5‐HT_2Breceptor antagonist PRX‐08066 in NET cell lines (KRJ‐I, H720) and in the coculture system (KRJ‐I cells: fibroblastic HEK293 cells) using real time polymerase chain reaction, ELISA, Ki67 immunostaining, and flow cytometry‐based caspase 3 assays to assess antiproliferative and profibrotic signaling pathways.RESULTS: In the 5‐HT_2Bexpressing SI‐NET cell line, KRJ‐I, PRX‐08066 inhibited proliferation (IC₅₀4.6x10⁻⁹M) and 5‐HT secretion (6.9 × 10⁻⁹M) and decreased ERK1/2 phosphorylation and profibrotic growth factor synthesis and secretion (transforming growth factor beta 1 [TGFβ1], connective tissue growth factor [CTGF] and fibroblast growth factor [FGF2]). In the KRJ‐I:HEK293 coculture system, PRX‐08066 significantly decreased 5‐HT release (>60%), Ki67 (transcript and immunostaining: 20%‐80%),TGFβ1,CTGF, andFGF2transcription (20%‐50%) in the KRJ‐I cell line. 5‐HT itself stimulated HEK293 proliferation (25%) and synthesis ofTGFβ1,CTGFandFGF2. PRX‐08066 inhibition of KRJ‐I function reversed these effects in the coculture system.CONCLUSIONS: Targeting the 5‐HT_2Breceptor may be an effective antiproliferative and antifibrotic strategy for SI‐NETs because it inhibits tumor microenvironment fibroblasts as well as NET cells. Fibrosis and proliferation appear to be biologically interfaced neuroendocrine neoplasia domains. Cancer 2010. © 2010 American Cancer Society.

Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease’s range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids.